The use of monoclonal antibodies for therapy has gained increasing interest in recent years. The ability to influence an individual""s immune state by administering immunoglobulin of appropriate specificity has been considered a powerful approach to disease control and prevention. Therapeutic efficacy of certain monoclonal antibodies in anti-tumor treatment has been documented. See e.g., Sears, H. F. et al., (1984) J. Biol. Resp. Modif. 3:138.
Viral specific antibodies can be therapeutically useful for treatment of viral infections. Antibodies directed against some components of a virus can neutralize the virus. Antibodies which fix complement (C1-C9) cause lysis of cells carrying viral antigens or directly damage enveloped viruses. Furthermore, antibodies that bind to Fc receptors on the surface of phagocytic cells can also cause antibody-dependent cell-mediated cytotoxicity of virus-infected cells.
Recently, monoclonal antibodies have been developed against the exterior glycoprotein gp120 of the human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS). See, Fung, S. C. et al., BioTechnology 5:940 (1987). The antibodies are capable of inhibiting the infection of susceptible T cells by free virions. The antibodies also inhibit the fusion between HIV-infected cells and uninfected cells which results in the formation of multinucleated giant cells (syncytia), a mechanism implicated as a major route of viral transmission and T cell death. These HIV-neutralizing antibodies have applications in therapy and prevention of AIDS.
Most presently available monoclonal antibodies, including antiviral monoclonal antibodies, are murine antibodies. The production of human antibodies by somatic cell fusion is generally difficult. Techniques for production of monoclonal antibodies in the mouse, however, are well established and allow for preparation of monoclonal antibodies against virtually any antigen.
Murine antibodies, however, have several drawbacks which impede their use in human therapy. As foreign proteins, murine antibodies often evoke counteracting immune reactions which may reduce or destroy their therapeutic effectiveness. In addition, murine antibodies can elicit allergic or hypersensitivity reactions in patients. Unfortunately, the need for readministration in therapy increases the likelihood that these immune reactions will occur in patients.
One way to ameliorate the problems associated with the in vivo use of a murine antibody is to convert the murine antibody to a xe2x80x9cchimericxe2x80x9d antibody. The chimeric antibody consists of the variable region of the murine antibody joined to a human constant region. See, e.g., Morrison, S. L. et al. (1984) xe2x80x9cChimeric Human Antibody Molecules: Mouse Antigen-binding Domains with Human Constant Region Domainsxe2x80x9d Proc. Natl. Acad. Sci. USA 81:6851; Neuberger, M. S. and Rabbits, T. H. xe2x80x9cProduction of Chimeric Antibodiesxe2x80x9d PCT Application No. PCT/GB85 00392. Because the chimeric antibody has a human constant region (the region which is largely responsible for inducing immune response against antibody), it is less likely to evoke an anti-murine immune response in humans. Furthermore, the human constant region may provide for an antibody with a longer half life and better effector function in humans.
A number of studies have described chimeric murine/human immunoglobulins. See, e.g., Sun, L. K. et al., (1987) Proc. Natl. Acad. Sci. USA 84:214; Liu, A. Y. et al., (1987) J. Immunol. 139:3521; Sahagan, B. G. et al., (1986) J. Immunol. 137:1066, Liu, A. Y. et al., (1987) Proc. Natl. Acad. Sci. USA 84:3439.
This invention pertains to chimeric viral neutralizing immunoglobulins, particularly HIV-neutralizing immunoglobulins, comprising a viral-specific antigen binding (variable) region of nonhuman origin and a constant region of human origin. The chimeric immunoglobulins, prepared by genetic engineering techniques, retain the viral neutralizing activity of the parent, nonhuman immunoglobulin from which they are derived. The chimeric immunoglobulins are useful for immuno-therapy of viral-mediated diseases such as AIDS.